The opioid system plays a fundamental role in the pathogenesis of AIDS. Brain regions expressing a high number/density of opioid receptors, such as the striatum and hippocampus, display increased viral load and are preferentially decimated by HIV infection. The progression to AIDS dementia in HIV-positive individuals may also be markedly accelerated in opiate drug abusers. Although the virus itself propagates in microglia and astroglia, HIV-1 proteins such as gp120 and Tat, are subsequently released and cause degeneration in neighboring neurons. "Opiates" (substances derived from the opium poppy, such as heroin) or analogues (e. g., OxyContin) are popular drugs of abuse. Although many aspects of HIV are caused indirectly by infected macrophages/microglial cells, direct toxic effects of the viral proteins themselves can be seen in isolated neurons. This direct neurotoxicity is exacerbated by mu opiate drugs. This proposal focuses on the interactions between mu opioids and HIV-1 proteins that result in direct synergistic neurotoxicity. Morphine synergistically increases Tat neurotoxicity via a pathway that is mediated in part by caspase-3. Our hypothesis is that opiates exacerbate neurodegenerative effects of HIV-1 by disrupting cellular homeostasis and increasing the probability of pro-apoptotic intracellular events. Disruptions in premitochondrial pathways involving PI3K, Akt, PTEN, calcium, calcineurin, and GSKSbeta will be examined for effects on both caspase- 3 dependent and independent (endonuclease-G) cell death using pharmacological, transfection (silencing/ overexpression vectors) and genetic strategies [caspase-3(-/-) and PTEN(-) mice]. Complementary in vivo/ in vitro approaches will identify the mechanisms by which mu opiates affect the survival of gp120/Tat- compromised striatal neurons. Aim 1 will explore the mechanisms by which opiate drugs exacerbate gp120/ Tat-induced neuronal death in vitro. Aim 2 will identify the effects of opiates on gp12Q7Tat-induced neurotoxicity in vivo using conditional Tat and gp120 expressing transgenic mice, and caspase-3 knockout and PTEN-deficient mice injected intrastriatally with Tat/gp120. Our long-term goal is to define the mechanisms by which opiate drug abuse contributes to neurodegeneration accompanying HIVE in the CNS, and to identify the underlying signaling pathways that could be targeted for therapeutic intervention.